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19 June 2015

14 Pages

Doxycycline and Tigecycline: Two Friendly Drugs with a Low Association with Clostridium Difficile Infection

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1
Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan 70043, Taiwan
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Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng Li Road, Tainan 70403, Taiwan
3
Graduate Institute of Clinical Medicine, National Health Research Institutes, Tainan 70403, Taiwan
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Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Medical College, Tainan 70102, Taiwan
Antibiotics2015, 4(2), 216-229;https://doi.org/10.3390/antibiotics4020216
This article belongs to the Special Issue Clostridium difficile Infection
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Abstract

Clostridium difficile infection (CDI) is known to be associated with prior exposure to many classes of antibiotics. Standard therapy for CDI (i.e., metronidazole and vancomycin) is associated with high recurrence rates. Although tetracycline derivatives such as tetracycline, doxycycline or tigecycline are not the standard therapeutic choices for CDI, they may serve as an alternative or a component of combination therapy. Previous tetracycline or doxycycline usage had been shown to have less association with CDI development. Tigecycline, a broad-spectrum glycylcycline with potency against many gram-positive or gram-negative pathogens, had been successfully used to treat severe or refractory CDI. The in vitro susceptibility of C. difficile clinical isolates to tigecycline in many studies showed low minimal inhibitory concentrations. Tigecycline can suppress in vitro toxin production in both historical and hypervirulent C. difficile strains and reduce spore production in a dose-dependent manner. Tetracycline compounds such as doxycycline, minocycline, and tigecycline possess anti-inflammatory properties that are independent of their antibiotic activity and may contribute to their therapeutic effect for CDI. Although clinical data are limited, doxycycline is less likely to induce CDI, and tigecycline can be considered one of the therapeutic choices for severe or refractory CDI.

1. Clinical Impact of Clostridium Difficile Infections

Nosocomial diarrhea is a common complication in hospitalized patients and contributes to increased morbidity and mortality and prolonged hospitalization [1,2]. Infectious diarrhea accounts for 10%–30% of nosocomial diarrhea [3]. Clostridium difficile infection (CDI) is the most well-known disease within the etiology of nosocomial infectious diarrhea. Moreover, C. difficile is the major cause of nosocomial antibiotic-associated diarrhea through the production of toxins A and B. The CDI disease pattern ranges from mild diarrhea to pseudomembranous colitis, toxic megacolon or colon perforation [4]. The 30-day attributable mortality rate in CDI cases is 6.9%; this rate is higher in patients who developed toxic megacolon, ranging from 25% to 40% [5,6]. C. difficile is frequently transmitted in healthcare settings via medical care workers. Therefore, CDI represents an important infection control issue [7].
The incidence of CDI has been increasing in recent years with sporadic outbreaks. The most well-known event was the CDI outbreak in Quebec, Canada in 2003. In this outbreak, CDI was the attributable cause of death in 117 (6.9%) cases out of 1703 patients and was a contributing factor in an additional 127 (7.5%) deaths [6]. In the United States, the number of CDI cases reported in 2005 (84 per 100,000) was nearly three times the number reported in 1996 (31 per 100,000) [4]. A recent multistate active surveillance study in the US revealed alarming national data concerning CDI that was indicative of a persistent health threat. In 2011, the estimated number of incident CDI cases was more than 453,000, and the crude incidence of community-associated and healthcare-associated CDI cases was 48.2 and 92.8 episodes per 100,000 persons in the US, respectively [8]. Of greater concern is the increase in severe and fatal infections [4]. The incidence of CDI at a medical center in southern Taiwan was 42.6 cases per 100,000 patient-days or 3.4 cases per 1000 discharges between January 2007 and March 2008 [9]. Notably, the incidence of toxigenic C. difficile colonization was higher, accounting for 84.8 cases/100,000 patient-days or 73.0/1000 patients at a regional hospital from 2011 to 2012 [10].

3. Doxycycline—Varied Susceptibility Data In Vitro but High Gut Tissue Concentrations

Before the susceptibility data of tetracycline for C. difficile isolates can be interpreted and compared, the important issue of the susceptible or resistant breakpoint must be addressed. No susceptible or resistant breakpoint for doxycycline was recommended from the Clinical and Laboratory Standards Institutes (CLSI), British Society for Antimicrobial Chemotherapy (BSAC) or European Committee on Antimicrobial Susceptibility Testing (EUCAST). Moreover, the susceptibility of tetracycline or its derivatives has rarely been reported for C. difficile isolates, making international comparisons difficult. This lack is at least partially related to the limited pharmacological data available for doxycycline at the target site (the intestinal mucosa) and the lack of a correlation between clinical treatment and the therapeutic outcome of doxycycline, which is not commonly used for CDI.
Although the susceptibility of C. difficile isolates to tetracycline varied geographically, most isolates reported in Europe were susceptible to tetracycline derivatives, with resistance rates of less than 10% [29,30,31,32]. The resistance rates of doxycycline in C. difficile isolates from animal products, animal stools, or soil were low, ranging from 0% to 2.1% as shown in Table 1 [33,34,35]. However, the susceptibility data for clinical C. difficile isolates varied significantly in a limited number of reports. A total of 11% of 43 isolates from Spain were doxycycline-resistant using a resistance criterion of minimal inhibitory concentration (MIC) >2 μg/mL [36]. Doxycycline resistance defined as a doxycycline MIC ≥8 μg/mL was noted in nearly 40% of 317 clinical isolates from Germany [37]. In contrast, all 48 clinical isolates in Israel were susceptible to doxycycline (MIC range: 0.016–0.38 g/mL) [38]. Even with the existence of a substantial degree of doxycycline resistance in clinical strains, a preventive or therapeutic role for doxycycline in C. difficile infection cannot be excluded completely because high doxycycline concentrations are present in bowel tissue after oral administration. Oral intake of 200 mg of doxycycline every 4–6 h resulted in a serum concentration of 4.0 ± 0.3 mg/L, ileum concentration of 7.5 ± 1.2 mg/L, and colon concentration of 3.9 ± 0.3 mg/L [39]. Theoretically, the high bowel tissue concentration may render doxycycline effective against C. difficile strains with higher MICs, but the drug levels in the intestinal lumen where C. difficile vegetative cells reside is likely to be the critical variable for the prevention or treatment of CDI.

4. Doxycycline—Protective Effect against CDI in Clinics?

Some reports have discussed the connection between doxycycline and CDI [40,41,42], but no information is available concerning minocycline. Although CDI was noted after doxycycline prophylaxis for malaria [43], doxycycline was associated with a decreased incidence of CDI in recent studies. Doxycycline was associated with a reduced risk of CDI (odds ratio, 0.41) in a retrospective case-control study that compared 1142 cases of hospital-acquired CDI from 1999 through 2005 with 3351 controls matched for facility [40]. In another study that used a multivariable model to adjust for confounding factors, the rate of CDI was 27% lower for each day of doxycycline administration compared to a patient without doxycycline therapy (hazard ratio, 0.73) [41]. A pharmacotherapy review concluded that doxycycline had protective effects against the development of CDI [42]. In contrast to the studies in Europe, tetracycline resistance was present in more than 30% of C. difficile isolates in China [32,44,45,46]. Thus, the preventive effect of tetracycline derivatives for CDI warrants confirmation by further clinical observation.
Table 1. In vitro susceptibility of doxycycline and tigecycline against Clostridium difficile isolates.

5. Tigecycline—Good In Vitro Susceptibility but Bad for Gut Microbiota

Tigecycline is a new generation tetracycline derivative. Although there is no CLSI breakpoint of tigecycline for C. difficile, in vitro susceptibility studies of clinical C. difficile isolates to tigecycline showed excellent antibacterial activity [29,30,47,48,49,50,51] (Table 1). For example, two (2.4%) strains from a collection of 83 toxigenic C. difficile isolates from Polish hospitals were resistant to tetracycline, while all of the strains were sensitive to tigecycline according to the latest EUCAST breakpoint (MIC <0.25 μg/mL).
Although tigecycline has the capability to inhibit toxin production or spore formation, its broad-spectrum antibacterial activity on gut microbiota renders its usage a risk factor for CDI. Tigecycline treatment resulted in major shifts in the gut microbiota in mice, including a decrease in Bacteroidetes levels and an increase in Proteobacteria levels, which made the treated mice susceptible to CDI [52]. Such a change in gut microbiota could last for weeks, as evidenced by the findings that the recovery of the bacterial community was incomplete and diversity was lower compared to untreated controls 5 weeks after the cessation of tigecycline treatment [52]. However, tigecycline instillation reduced competing microflora, including Bacteroides and Bifidobacteria, in an in vitro human gut model but did not induce C. difficile proliferation or cytotoxin production [53].

6. Tigecycline—Beyond Antibacterial Effects against C. Difficile

Notably, tigecycline can suppress spore formation in vitro [24], and this finding was linked to the potential efficacy for tigecycline therapy against recurrent CDI. Furthermore, tigecycline did not promote the growth or toxin production of C. difficile in a mouse model, and concurrent administration of tigecycline prevented clindamycin-induced promotion of C. difficile growth in the cecal contents [54]. Tigecycline can suppress in vitro toxin production in both historical and hypervirulent C. difficile strains and reduce spore production in a dose-dependent manner [55,56]. These experimental data partially explain the fact that tigecycline therapy was associated with a low recurrence rate of CDI [57,58]. In contrast, metronidazole and vancomycin, two standard antimicrobial drugs for CDI, had a similar suppressive effect on toxin production but less suppression on spore formation [55], which provided an explanation as to why metronidazole or vancomycin therapy for CDI was related to a higher recurrence rate [59,60].
Tetracycline compounds possess anti-inflammatory properties independent of their antibiotic activity that may contribute to their therapeutic effects on CDI [61]. Tigecycline can attenuate staphylococcal superantigen-induced T-cell proliferation and the production of cytokines (i.e., IL-1β, IL-6, and TNF-α) and chemokines (i.e., MIP-1α and MIP-1β) [62]. For example, tigecycline therapy significantly reduced the concentrations of inflammatory pulmonary cytokine (i.e., IL-1β, IL-12, IFN-γ, and TNF-α) and chemokine concentrations (i.e., MIG, MIP-1α, and IP-10) in a murine model of Mycoplasma pneumoniae pneumonia [63]. Moreover, tigecycline prevented the lipopolysaccharide-induced release of pro-inflammatory and apoptotic mediators in neuronal cells [64], thereby exhibiting a so-called “neuroprotective effect”. In CDI cases, these anti-inflammatory effects may contribute additional therapeutic benefits to intestinal inflammation.

7. Tigecycline—Treatment of CDI

Metronidazole and vancomycin are currently regarded as the primary therapy for CDI, although the choice of initial therapy depends on the severity of disease. Metronidazole is the agent of choice for most patients with mild to moderate CDI and can be administered via the oral or intravenous routes [65]. Oral vancomycin is recommended for patients with severe CDI [65]. The facilitation of fecal colonization by vancomycin-resistant enterococci is a potential drawback of oral vancomycin [66]. Nevertheless, recurrent CDI was noted with either metronidazole or vancomycin therapy and was more difficult to manage than the initial CDI episodes [59,60]. The newer antibiotic fidaxomicin showed promising therapeutic results, with clinical cure rates similar to those of vancomycin and lower recurrence rates [67]. Nevertheless, fidaxomicin is expensive and not available worldwide.
Although tetracycline derivatives such as doxycycline or tigecycline are not the standard therapeutic choices for CDI, they may serve as alternatives or components of combination therapy for refractory CDI. Although tigecycline usage might be a risk factor for CDI, successful treatment of CDI using a tigecycline-containing combination regimen had been reported. The dosage of tigecycline commonly used was an intravenous loading dose of 100 mg, followed by 50 mg every 12 h. In 2009, Herpers and colleagues first described four cases of severe refractory CDI that were successfully treated by tigecycline monotherapy or combination therapy with oral vancomycin [68]. Then, Lu successfully treated another case of severe and refractory CDI with tigecycline and metronidazole for 14 days [69]. One patient with recurrent CDI that was refractory to vancomycin and metronidazole was effectively managed by the combination of intravenous tigecycline, oral rifaximin and oral vancomycin [70], while a second patient was managed by intravenous tigecycline and oral rifaximin [71]. Recently, seven cases of severe CDI reported by Nicholas et al. were treated with an antibiotic cocktail containing intravenous tigecycline and metronidazole in combination with oral vancomycin, which led to clinical cure in six (85.7%) cases. The sustained response at 28 days was 100% among five evaluable cases [72] (Table 2). Thus, these clinical experiences indicated that tigecycline could be a potential component of combination therapy for CDI, especially in severe or refractory cases.
Table 2. Clinical reports of the therapeutic efficacy of tigecycline for Clostridium difficile infection (CDI).
In contrast, conflicting clinical data had argued against the use of tigecycline-containing regimens for CDI. Ashley et al. compared 18 patients with severe CDI treated with tigecycline-containing regimens in which tigecycline was administered for at least 48 h, 17 patients administered oral vancomycin and intravenous metronidazole and one patient administered oral fidaxomicin compared with 26 patients receiving oral vancomycin and metronidazole therapy [73]. There were no differences in the need for colectomy, recurrence, or mortality between the two groups. Kopterides et al. reported a 70-year-old man with severe CDI that eventually succumbed to complications of his illness despite three-week tigecycline therapy in conjunction with vancomycin, metronidazole and intravenous immunoglobulin. Additionally, the specific challenges related to tigecycline therapy (i.e., the development of Proteus mirabilis bacteremia and colonization with tigecycline-resistant Acinetobacter baumannii) should not be ignored [74].

8. Conclusions

In conclusion, prior exposure to doxycycline is less likely to induce CDI. The correlation between prior tigecycline therapy and subsequent CDI is controversial. Nevertheless, tigecycline has an inhibitory effect on toxin production, spore formation, and inflammation and may serve as a potential component of combination therapy for severe or refractory CDI.

Acknowledgment

This article was partially supported by grants from the Ministry of Science & Technology, (102-2628-B-006-015-MY3 and 104-2321-B-006-020) and Ministry of Health & Welfare (MOHW104-TDU-B-211-113002), Taiwan.

Author Contributions

Yuan-Pin Hung wrote the article. Hsiao-Ju Lin and Hsiao-Chieh Liu searched the database. Yi-Hui Wu and Jen-Chieh Lee analyzed the data. Pei-Jane Tsai and Wen-Chien Ko revised the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bunnapradist, S.; Neri, L.; Wong, W.; Lentine, K.L.; Burroughs, T.E.; Pinsky, B.W.; Takemoto, S.K.; Schnitzler, M.A. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. Am. J. Kidney Dis. 2008, 51, 478–486. [Google Scholar] [CrossRef] [PubMed]
  2. Roddie, C.; Paul, J.P.; Benjamin, R.; Gallimore, C.I.; Xerry, J.; Gray, J.J.; Peggs, K.S.; Morris, E.C.; Thomson, K.J.; Ward, K.N. Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: A previously unrecognized cause of morbidity. Clin. Infect. Dis. 2009, 49, 1061–1068. [Google Scholar] [CrossRef] [PubMed]
  3. Polage, C.R.; Solnick, J.V.; Cohen, S.H. Nosocomial diarrhea: Evaluation and treatment of causes other than Clostridium difficile. Clin. Infect. Dis. 2012, 55, 982–989. [Google Scholar] [CrossRef] [PubMed]
  4. Kelly, C.P.; LaMont, J.T. Clostridium difficile—More difficult than ever. N. Engl. J. Med. 2008, 359, 1932–1940. [Google Scholar] [CrossRef] [PubMed]
  5. Kuijper, E.J.; van Dissel, J.T.; Wilcox, M.H. Clostridium difficile: Changing epidemiology and new treatment options. Curr. Opin. Infect. Dis. 2007, 20, 376–383. [Google Scholar] [CrossRef] [PubMed]
  6. Loo, V.G.; Poirier, L.; Miller, M.A.; Oughton, M.; Libman, M.D.; Michaud, S.; Bourgault, A.M.; Nguyen, T.; Frenette, C.; Kelly, M.; et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N. Engl. J. Med. 2005, 353, 2442–2449. [Google Scholar] [CrossRef] [PubMed]
  7. Bartlett, J.G. Narrative review: The new epidemic of Clostridium difficile-associated enteric disease. Ann. Intern. Med. 2006, 145, 758–764. [Google Scholar] [CrossRef] [PubMed]
  8. Lessa, F.C.; Mu, Y.; Bamberg, W.M.; Beldavs, Z.G.; Dumyati, G.K.; Dunn, J.R.; Farley, M.M.; Holzbauer, S.M.; Meek, J.I.; Phipps, E.C.; et al. Burden of Clostridium difficile infection in the united states. N. Engl. J. Med. 2015, 372, 825–834. [Google Scholar] [CrossRef] [PubMed]
  9. Chung, C.H.; Wu, C.J.; Lee, H.C.; Yan, J.J.; Chang, C.M.; Lee, N.Y.; Chen, P.L.; Lee, C.C.; Hung, Y.P.; Ko, W.C. Clostridium difficile infection at a medical center in southern Taiwan: Incidence, clinical features and prognosis. J. Microbiol. Immunol. Infect. 2010, 43, 119–125. [Google Scholar] [CrossRef]
  10. Hung, Y.P.; Lin, H.J.; Wu, T.C.; Liu, H.C.; Lee, J.C.; Lee, C.I.; Wu, Y.H.; Wan, L.; Tsai, P.J.; Ko, W.C. Risk factors of fecal toxigenic or non-toxigenic Clostridium difficile colonization: Impact of toll-like receptor polymorphisms and prior antibiotic exposure. PLoS ONE 2013, 8, e69577. [Google Scholar] [CrossRef] [PubMed]
  11. Riggs, M.M.; Sethi, A.K.; Zabarsky, T.F.; Eckstein, E.C.; Jump, R.L.; Donskey, C.J. Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin. Infect. Dis. 2007, 45, 992–998. [Google Scholar] [CrossRef] [PubMed]
  12. Ryan, J.; Murphy, C.; Twomey, C.; Paul Ross, R.; Rea, M.C.; MacSharry, J.; Sheil, B.; Shanahan, F. Asymptomatic carriage of Clostridium difficile in an Irish continuing care institution for the elderly: Prevalence and characteristics. Ir. J. Med. Sci. 2010, 179, 245–250. [Google Scholar] [CrossRef] [PubMed]
  13. Ubeda, C.; Taur, Y.; Jenq, R.R.; Equinda, M.J.; Son, T.; Samstein, M.; Viale, A.; Socci, N.D.; van den Brink, M.R.; Kamboj, M.; et al. Vancomycin-resistant enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J. Clin. Investig. 2010, 120, 4332–4341. [Google Scholar] [CrossRef] [PubMed]
  14. Hung, Y.P.; Tsai, P.J.; Hung, K.H.; Liu, H.C.; Lee, C.I.; Lin, H.J.; Wu, Y.H.; Wu, J.J.; Ko, W.C. Impact of toxigenic Clostridium difficile colonization and infection among hospitalized adults at a district hospital in southern Taiwan. PLoS ONE 2012, 7, e42415. [Google Scholar] [CrossRef] [PubMed]
  15. Britton, R.A.; Young, V.B. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 2012, 20, 313–319. [Google Scholar] [CrossRef] [PubMed]
  16. Vesteinsdottir, I.; Gudlaugsdottir, S.; Einarsdottir, R.; Kalaitzakis, E.; Sigurdardottir, O.; Bjornsson, E.S. Risk factors for Clostridium difficile toxin-positive diarrhea: A population-based prospective case-control study. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 2601–2610. [Google Scholar] [CrossRef] [PubMed]
  17. Stevens, V.; Dumyati, G.; Fine, L.S.; Fisher, S.G.; van Wijngaarden, E. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin. Infect. Dis. 2011, 53, 42–48. [Google Scholar] [CrossRef] [PubMed]
  18. McFarland, L.V.; Clarridge, J.E.; Beneda, H.W.; Raugi, G.J. Fluoroquinolone use and risk factors for Clostridium difficile-associated disease within a veterans administration health care system. Clin. Infect. Dis. 2007, 45, 1141–1151. [Google Scholar] [CrossRef] [PubMed]
  19. McCusker, M.E.; Harris, A.D.; Perencevich, E.; Roghmann, M.C. Fluoroquinolone use and Clostridium difficile-associated diarrhea. Emerg. Infect. Dis. 2003, 9, 730–733. [Google Scholar] [CrossRef] [PubMed]
  20. Delaney, J.A.; Dial, S.; Barkun, A.; Suissa, S. Antimicrobial drugs and community-acquired Clostridium difficile-associated disease, UK. Emerg. Infect. Dis. 2007, 13, 761–763. [Google Scholar] [CrossRef] [PubMed]
  21. Wilcox, M.H.; Freeman, J.; Fawley, W.; MacKinlay, S.; Brown, A.; Donaldson, K.; Corrado, O. Long-term surveillance of cefotaxime and piperacillin-tazobactam prescribing and incidence of Clostridium difficile diarrhoea. J. Antimicrob. Chemother. 2004, 54, 168–172. [Google Scholar] [CrossRef] [PubMed]
  22. Settle, C.D.; Wilcox, M.H.; Fawley, W.N.; Corrado, O.J.; Hawkey, P.M. Prospective study of the risk of Clostridium difficile diarrhoea in elderly patients following treatment with cefotaxime or piperacillin-tazobactam. Aliment. Pharmacol. Ther. 1998, 12, 1217–1223. [Google Scholar] [CrossRef] [PubMed]
  23. Alston, W.K.; Ahern, J.W. Increase in the rate of nosocomial Clostridium difficile-associated diarrhoea during shortages of piperacillin-tazobactam and piperacillin. J. Antimicrob. Chemother. 2004, 53, 549–550. [Google Scholar] [CrossRef] [PubMed]
  24. Pultz, N.J.; Donskey, C.J. Effect of antibiotic treatment on growth of and toxin production by Clostridium difficile in the cecal contents of mice. Antimicrob. Agents Chemother. 2005, 49, 3529–3532. [Google Scholar] [CrossRef] [PubMed]
  25. Mendez, M.N.; Gibbs, L.; Jacobs, R.A.; McCulloch, C.E.; Winston, L.; Guglielmo, B.J. Impact of a piperacillin-tazobactam shortage on antimicrobial prescribing and the rate of vancomycin-resistant enterococci and Clostridium difficile infections. Pharmacotherapy 2006, 26, 61–67. [Google Scholar] [CrossRef] [PubMed]
  26. Rodriguez, S.; Hernandez, M.B.; Tarchini, G.; Zaleski, M.; Vatanchi, M.; Cardona, L.; Castro-Pavia, F.; Schneider, A. Risk of Clostridium difficile infection in hospitalized patients receiving metronidazole for a non-c difficile infection. Clin. Gastroenterol. Hepatol. 2014, 12, 1856–1861. [Google Scholar] [CrossRef] [PubMed]
  27. Hebert, C.; Du, H.; Peterson, L.R.; Robicsek, A. Electronic health record-based detection of risk factors for Clostridium difficile infection relapse. Infect. Control Hosp. Epidemiol. 2013, 34, 407–414. [Google Scholar] [CrossRef] [PubMed]
  28. Archimandritis, A.; Souyioultzis, S.; Katsorida, M.; Tzivras, M. Clostridium difficile colitis associated with a “triple” regimen, containing clarithromycin and metronidazole, to eradicate helicobacter pylori. J. Intern. Med. 1998, 243, 251–253. [Google Scholar] [CrossRef] [PubMed]
  29. Rashid, M.U.; Dalhoff, A.; Weintraub, A.; Nord, C.E. In vitro activity of mcb3681 against Clostridium difficile strains. Anaerobe 2014, 28, 216–219. [Google Scholar] [CrossRef] [PubMed]
  30. Rashid, M.U.; Lozano, H.M.; Weintraub, A.; Nord, C.E. In vitro activity of cadazolid against Clostridium difficile strains isolated from primary and recurrent infections in Stockholm, Sweden. Anaerobe 2013, 20, 32–35. [Google Scholar] [CrossRef] [PubMed]
  31. Barbut, F.; Mastrantonio, P.; Delmee, M.; Brazier, J.; Kuijper, E.; Poxton, I. Prospective study of Clostridium difficile infections in Europe with phenotypic and genotypic characterisation of the isolates. Clin. Microbiol. Infect. 2007, 13, 1048–1057. [Google Scholar] [CrossRef] [PubMed]
  32. Huang, H.; Fang, H.; Weintraub, A.; Nord, C.E. Distinct ribotypes and rates of antimicrobial drug resistance in Clostridium difficile from Shanghai and Stockholm. Clin. Microbiol. Infect. 2009, 15, 1170–1173. [Google Scholar] [CrossRef] [PubMed]
  33. Kouassi, K.A.; Dadie, A.T.; N’Guessan, K.F.; Dje, K.M.; Loukou, Y.G. Clostridium perfringens and Clostridium difficile in cooked beef sold in cote d’ivoire and their antimicrobial susceptibility. Anaerobe 2014, 28, 90–94. [Google Scholar] [CrossRef] [PubMed]
  34. Simango, C.; Mwakurudza, S. Clostridium difficile in broiler chickens sold at market places in Zimbabwe and their antimicrobial susceptibility. Int. J. Food Microbiol. 2008, 124, 268–270. [Google Scholar] [CrossRef] [PubMed]
  35. Simango, C. Prevalence of Clostridium difficile in the environment in a rural community in Zimbabwe. Trans. R. Soc. Trop. Med. Hyg. 2006, 100, 1146–1150. [Google Scholar] [CrossRef] [PubMed]
  36. Alcala, L.; Martin, A.; Marin, M.; Sanchez-Somolinos, M.; Catalan, P.; Pelaez, T.; Bouza, E. The undiagnosed cases of Clostridium difficile infection in a whole nation: Where is the problem? Clin. Microbiol. Infect. 2012, 18, E204–E213. [Google Scholar] [CrossRef] [PubMed]
  37. Schmidt, C.; Loffler, B.; Ackermann, G. Antimicrobial phenotypes and molecular basis in clinical strains of Clostridium difficile. Diagn. Microbiol. Infect. Dis. 2007, 59, 1–5. [Google Scholar] [CrossRef] [PubMed]
  38. Bishara, J.; Bloch, Y.; Garty, M.; Behor, J.; Samra, Z. Antimicrobial resistance of Clostridium difficile isolates in a tertiary medical center, israel. Diagn. Microbiol. Infect. Dis. 2006, 54, 141–144. [Google Scholar] [CrossRef] [PubMed]
  39. Hojer, H.; Wetterfors, J. Concentration of doxycycline in bowel tissue and postoperative infections. Scand. J. Infect. Dis. Suppl. 1976, 9, 100–105. [Google Scholar]
  40. Baxter, R.; Ray, G.T.; Fireman, B.H. Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients. Infect. Control Hosp. Epidemiol. 2008, 29, 44–50. [Google Scholar] [CrossRef] [PubMed]
  41. Doernberg, S.B.; Winston, L.G.; Deck, D.H.; Chambers, H.F. Does doxycycline protect against development of Clostridium difficile infection? Clin. Infect. Dis. 2012, 55, 615–620. [Google Scholar] [CrossRef] [PubMed]
  42. Turner, R.B.; Smith, C.B.; Martello, J.L.; Slain, D. Role of doxycycline in Clostridium difficile infection acquisition. Ann. Pharmacother. 2014, 48, 772–776. [Google Scholar] [CrossRef] [PubMed]
  43. Golledge, C.L.; Riley, T.V. Clostridium difficile-associated diarrhoea after doxycycline malaria prophylaxis. Lancet 1995, 345, 1377–1378. [Google Scholar] [CrossRef]
  44. Dong, D.; Zhang, L.; Chen, X.; Jiang, C.; Yu, B.; Wang, X.; Peng, Y. Antimicrobial susceptibility and resistance mechanisms of clinical Clostridium difficile from a Chinese tertiary hospital. Int. J. Antimicrob. Agents 2013, 41, 80–84. [Google Scholar] [CrossRef] [PubMed]
  45. Huang, H.; Weintraub, A.; Fang, H.; Wu, S.; Zhang, Y.; Nord, C.E. Antimicrobial susceptibility and heteroresistance in Chinese Clostridium difficile strains. Anaerobe 2010, 16, 633–635. [Google Scholar] [CrossRef] [PubMed]
  46. Huang, H.; Wu, S.; Wang, M.; Zhang, Y.; Fang, H.; Palmgren, A.C.; Weintraub, A.; Nord, C.E. Clostridium difficile infections in a shanghai hospital: Antimicrobial resistance, toxin profiles and ribotypes. Int. J. Antimicrob. Agents 2009, 33, 339–342. [Google Scholar] [CrossRef] [PubMed]
  47. Lin, Y.C.; Huang, Y.T.; Tsai, P.J.; Lee, T.F.; Lee, N.Y.; Liao, C.H.; Lin, S.Y.; Ko, W.C.; Hsueh, P.R. Antimicrobial susceptibilities and molecular epidemiology of clinical isolates of Clostridium difficile in Taiwan. Antimicrob Agents Chemother 2011, 55, 1701–1705. [Google Scholar] [CrossRef] [PubMed]
  48. Hecht, D.W.; Galang, M.A.; Sambol, S.P.; Osmolski, J.R.; Johnson, S.; Gerding, D.N. In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob. Agents Chemother. 2007, 51, 2716–2719. [Google Scholar] [CrossRef] [PubMed]
  49. Edlund, C.; Sabouri, S.; Nord, C.E. Comparative in vitro activity of bay 12–8039 and five other antimicrobial agents against anaerobic bacteria. Eur. J. Clin. Microbiol. Infect. Dis. 1998, 17, 193–195. [Google Scholar] [CrossRef] [PubMed]
  50. Hawser, S.P. Activity of tigecycline against recent European clinical isolates of Clostridium difficile. Int. J. Antimicrob. Agents 2010, 35, 97–98. [Google Scholar] [CrossRef] [PubMed]
  51. Lachowicz, D.; Pituch, H.; Obuch-Woszczatynski, P. Antimicrobial susceptibility patterns of Clostridium difficile strains belonging to different polymerase chain reaction ribotypes isolated in Poland in 2012. Anaerobe 2015, 31, 37–41. [Google Scholar] [CrossRef] [PubMed]
  52. Bassis, C.M.; Theriot, C.M.; Young, V.B. Alteration of the murine gastrointestinal microbiota by tigecycline leads to increased susceptibility to Clostridium difficile infection. Antimicrob. Agents Chemother. 2014, 58, 2767–2774. [Google Scholar] [CrossRef] [PubMed]
  53. Baines, S.D.; Saxton, K.; Freeman, J.; Wilcox, M.H. Tigecycline does not induce proliferation or cytotoxin production by epidemic Clostridium difficile strains in a human gut model. J. Antimicrob. Chemother. 2006, 58, 1062–1065. [Google Scholar] [CrossRef] [PubMed]
  54. Jump, R.L.; Li, Y.; Pultz, M.J.; Kypriotakis, G.; Donskey, C.J. Tigecycline exhibits inhibitory activity against Clostridium difficile in the colon of mice and does not promote growth or toxin production. Antimicrob. Agents Chemother. 2011, 55, 546–549. [Google Scholar] [CrossRef] [PubMed]
  55. Aldape, M.J.; Heeney, D.D.; Bryant, A.E.; Stevens, D.L. Tigecycline suppresses toxin a and b production and sporulation in Clostridium difficile. J. Antimicrob. Chemother. 2015, 70, 153–159. [Google Scholar] [CrossRef] [PubMed]
  56. Theriot, C.M.; Schumacher, C.A.; Bassis, C.M.; Seekatz, A.M.; Young, V.B. Effects of tigecycline and vancomycin administration on established Clostridium difficile infection. Antimicrob. Agents Chemother. 2015, 59, 1596–1604. [Google Scholar] [CrossRef] [PubMed]
  57. Larson, K.C.; Belliveau, P.P.; Spooner, L.M. Tigecycline for the treatment of severe Clostridium difficile infection. Ann. Pharmacother. 2011, 45, 1005–1010. [Google Scholar] [CrossRef] [PubMed]
  58. Cheong, E.Y.; Gottlieb, T. Intravenous tigecycline in the treatment of severe recurrent Clostridium difficile colitis. Med. J. Aust. 2011, 194, 374–375. [Google Scholar] [PubMed]
  59. DuPont, H.L. The search for effective treatment of Clostridium difficile infection. N. Engl. J. Med. 2011, 364, 473–475. [Google Scholar] [CrossRef] [PubMed]
  60. Gerding, D.N.; Muto, C.A.; Owens, R.C., Jr. Treatment of Clostridium difficile infection. Clin. Infect. Dis. 2008, 46, S32–S42. [Google Scholar] [CrossRef] [PubMed]
  61. Dunston, C.R.; Griffiths, H.R.; Lambert, P.A.; Staddon, S.; Vernallis, A.B. Proteomic analysis of the anti-inflammatory action of minocycline. Proteomics 2011, 11, 42–51. [Google Scholar] [CrossRef] [PubMed]
  62. Saliba, R.; Paasch, L.; El Solh, A. Tigecycline attenuates staphylococcal superantigen-induced T-cell proliferation and production of cytokines and chemokines. Immunopharmacol. Immunotoxicol. 2009, 31, 583–588. [Google Scholar] [CrossRef] [PubMed]
  63. Salvatore, C.M.; Techasaensiri, C.; Tagliabue, C.; Katz, K.; Leos, N.; Gomez, A.M.; McCracken, G.H.; Hardy, R.D. Tigecycline therapy significantly reduces the concentrations of inflammatory pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia. Antimicrob. Agents Chemother. 2009, 53, 1546–1551. [Google Scholar] [CrossRef] [PubMed]
  64. Yagnik, R.M.; Benzeroual, K.E. Tigecycline prevents lps-induced release of pro-inflammatory and apoptotic mediators in neuronal cells. Toxicol. In Vitro 2013, 27, 686–693. [Google Scholar] [CrossRef] [PubMed]
  65. Zar, F.A.; Bakkanagari, S.R.; Moorthi, K.M.; Davis, M.B. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin. Infect. Dis. 2007, 45, 302–307. [Google Scholar] [CrossRef] [PubMed]
  66. Gerding, D.N. Is there a relationship between vancomycin-resistant enterococcal infection and Clostridium difficile infection? Clin. Infect. Dis. 1997, 25, S206–S210. [Google Scholar] [CrossRef] [PubMed]
  67. Bagdasarian, N.; Rao, K.; Malani, P.N. Diagnosis and treatment of Clostridium difficile in adults: A systematic review. JAMA 2015, 313, 398–408. [Google Scholar] [CrossRef] [PubMed]
  68. Herpers, B.L.; Vlaminckx, B.; Burkhardt, O.; Blom, H.; Biemond-Moeniralam, H.S.; Hornef, M.; Welte, T.; Kuijper, E.J. Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin. Infect. Dis. 2009, 48, 1732–1735. [Google Scholar] [CrossRef] [PubMed]
  69. Lu, C.L.; Liu, C.Y.; Liao, C.H.; Huang, Y.T.; Wang, H.P.; Hsueh, P.R. Severe and refractory Clostridium difficile infection successfully treated with tigecycline and metronidazole. Int. J. Antimicrob. Agents 2010, 35, 311–312. [Google Scholar] [CrossRef] [PubMed]
  70. Lao, D., 2nd; Chiang, T.; Gomez, E. Refractory Clostridium difficile infection successfully treated with tigecycline, rifaximin, and vancomycin. Case Rep. Med. 2012, 2012, e702910. [Google Scholar]
  71. El-Herte, R.I.; Baban, T.A.; Kanj, S.S. Recurrent refractory Clostridium difficile colitis treated successfully with rifaximin and tigecycline: A case report and review of the literature. Scand. J. Infect. Dis. 2012, 44, 228–230. [Google Scholar] [CrossRef] [PubMed]
  72. Britt, N.S.; Steed, M.E.; Potter, E.M.; Clough, L.A. Tigecycline for the treatment of severe and severe complicated Clostridium difficile infection. Infect. Dis. Ther. 2014, 3, 321–331. [Google Scholar] [CrossRef] [PubMed]
  73. Thomas, A.; Khan, F.; Uddin, N.; Wallace, M.R. Tigecycline for severe Clostridium difficile infection. Int. J. Infect. Dis. 2014, 26, 171–172. [Google Scholar] [CrossRef] [PubMed]
  74. Kopterides, P.; Papageorgiou, C.; Antoniadou, A.; Papadomichelakis, E.; Tsangaris, I.; Dimopoulou, I.; Armaganidis, A. Failure of tigecycline to treat severe Clostridium difficile infection. Anaesth. Intensive Care 2010, 38, 755–758. [Google Scholar] [PubMed]

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The Antimicrobial Stewardship Approach to Combating Clostridium Difficile
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